PROJECT SUMMARY ? Project 2 Digital breast tomosynthesis use has rapidly increased for breast cancer screening, outpacing evidence of effectiveness in community settings for women overall and for specific populations. Emerging evidence suggests tomosynthesis may lower recall rates while simultaneously improving cancer detection. However, critical questions remain: whether early reports of improved screening outcomes remain in beyond initial screening rounds and are sustainable in community settings; whether tomosynthesis outcomes vary based on woman, radiologist, or facility characteristics; whether tomosynthesis is equal to or outperforms supplemental screening; and whether additional cancers detected are likely to lead to reduced morbidity and mortality from breast cancer. With the rapid shift to tomosynthesis as the dominant screening modality, a thorough understanding of its effectiveness in community settings across subgroups of women is needed. In our current P01, using the rich data resource of the Breast Cancer Surveillance Consortium (BCSC), we have demonstrated the importance of multi-level factors, including woman, radiologist, and facility characteristics, on digital mammography screening outcomes. Given the quick uptake of tomosynthesis in the BCSC, it is now possible to examine outcomes of tomosynthesis screening in relation to multi-level factors and to quantify the benefit-harm balance. Our overall project objective is to identify the most effective screening strategies that incorporate new screening technologies in community practice based on women's risk factors and multi-level contextual factors. We hypothesize that tomosynthesis will perform better than digital mammography for some, but not all, women and that there are some women who may benefit from multi-modal screening. We will also evaluate whether tomosynthesis can reduce the need for supplemental screening ultrasound and/or magnetic resonance imaging (MRI) in women at high risk of a missed cancer on digital mammography. We specifically aim to determine: Aim 1) the benefits and harms of screening tomosynthesis compared to digital mammography based on women's characteristics and multi-level contextual factors, particularly among women at risk of poor screening outcomes (as determined in Project 1 and facilitated by the Biostatistics and Data Management Core); Aim 2) the observed benefits and harms of multi-modality screening (digital mammography with supplemental ultrasound and/or MRI) versus tomosynthesis alone; and Aim 3) the long- term benefits (e.g., deaths averted from breast cancer and life years gained) and harms from multi-modality screening versus tomosynthesis screening alone among women at higher risk for screening failures through simulation modeling (in conjunction with the Comparative Effectiveness Core). This project will fill critical knowledge gaps regarding the effectiveness of tomosynthesis and multi-modality screening, which we believe will have direct translation into actionable screening guidelines. 1